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Il-1 family variantsIl-1 family variants description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080241096, Il-1 family variants. Brief Patent Description - Full Patent Description - Patent Application Claims
This application claims the benefit of U.S. provisional patent application No. 60/843,311, filed Sep. 8, 2006 which is hereby incorporated by reference. FIELD OF THE INVENTIONThis application provides nucleic acids, polypeptides, compositions, assays, and methods relating to variants of IL-1Family members that signal through IL-1Rrp2. BACKGROUND OF THE INVENTIONThe IL-1 family includes several cytokines whose primary function is to mediate immune and inflammatory responses. The earliest members discovered were IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1ra), and IL-18 (previously known as IGIF and sometimes IL-1 gamma). Following the discovery of additional proteins with homology to these IL-1 family members, a nomenclature system was adopted in which IL-1 alpha is referred to as IL-1F1, IL-1 beta as IL-1F2, IL-1ra as IL-1F3 and IL-18 as IL-1F4. Seven additional cytokines have been classified as IL-1 family members based on amino acid sequence similarity, identity of gene structure, and predicted or known three-dimensional structure (Sims, J. E. et al., Trends Immunol 22:537, 2001; Dunn, E., et al., Trends Immunol 22:533, 2001; Dunn, E. F., et al., Biochemistry 42:10938, 2003; Schmitz et al. Immunity 23:479-490, 2005). IL-1 alpha, IL-1 beta and IL-1ra (IL-1F1-3, respectively) bind to receptors that are members of the immunoglobulin superfamily, the 80 kDa type I receptor (IL-1RI) and a 68 kDa type II receptor (IL-1RII), as well as a soluble proteolytic fragment of IL-1RII (sIL-1RII). Binding of IL-1 (alpha or beta) to the type I IL-1 receptor (IL-1R) results in recruitment of the IL-1R homolog, IL-1R accessory protein (IL-1 RAcP or AcP), which does not directly bind the ligands but is required for signal transduction (Sims et al. Trends Immunol 22; 537, 2001); binding of IL-1ra does not. Signaling by IL-18 is very similar, although IL-18 utilizes a different receptor complex (Born, T. L., et al., J Biol Chem 273:29445, 1998). IL-1F5, F6, F8 and F9 make use of the IL-1R-related protein 2 (IL-1Rrp2), with F6, F8 and F9 agonizing this receptor pathway, and IL-1F5 antagonizing it (Debets, R., et al., J Immunol 167:1440, 2001; Towne et al. 2004 J Biol Chem 279(14):13677) Several members of the IL-1 family (IL-1 alpha, IL-1 beta, IL-18, IL-1F7 and IL-33) are synthesized as precursor molecules that are proteolytically cleaved, by caspase-1 in the case of IL-1 beta and IL-18, and by an unidentified protease or proteases for IL-33, IL-1 alpha and IL-1F7. IL-1ra is activated by signal peptidase cleavage of a short peptide from the n-terminus. However, little is known about what, if any, processing occurs with the remaining family members. BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1 provides an alignment of the N-terminal portions of wild type IL-1F5, F6, F8 and F9. There is a (Met or Ile)-Xaa-Asp sequence present in each of F5, F6, F8 and F9, marked by underlining of the Met/Ile and the Asp residues. There is a similar “aliphatic amino acid-X-Aspartate or other polar amino acid” motif present in all IL-1 family members, and this can be used to align IL-1 family sequences. The consensus motif is indicated by @XD where @ may be an aliphatic amino acid such as Met or Ile and X is any one amino acid D is Asp. In FIG. 1, the sequences are lined up using the Met/Ile-Xaa-Asp motif (Met 11 in F5, Ile15 in F6, Ile14 in F8, and Ile27 in F9 respectively), so that the natural N-termini (with initiating methionines) lie at different distances upstream of the aliphatic amino acid, (, of the motif. FIG. 2 is the full length wild type amino acid sequences of IL-1F5, IL-1F6, IL-1F8 and IL-1F9. SUMMARY OF THE INVENTIONIn one aspect, the present invention provides an isolated IL-1F5 polypeptide that antagonizes signal transduction/activation through IL-1Rrp2, where the IL-1F5 polypeptide contains the sequence Met-Lys-Asp, which matches the consensus @XD depicted in FIG. 1, and wherein the polypeptide comprises nine amino acids on the N-terminal side of the above-referenced methionine. In one embodiment the IL-1F5 polypeptide is a human IL-1F5 polypeptide. In one embodiment, the IL-1F5 polypeptide of the invention comprises an amino acid sequence having a methionine at position ten of the amino acid sequence, position ten being relative to the N-terminal amino acid at position one of the amino acid sequence. In one embodiment, the IL-1F5 polypeptide of the invention comprises an amino acid sequence having a methionine at position ten of the amino acid sequence, position ten being relative to the N-terminal amino acid at position one of the amino acid sequence and an amino acid selected from the group consisting of valine and methionine at the N-terminal amino acid at position one. In one embodiment, the IL-1F5 polypeptide of the invention comprises an amino acid sequence having a methionine at position ten of the amino acid sequence, position ten being relative to the N-terminal amino acid at position one of the amino acid sequence and a leucine at position two of its amino acid sequence. In a particular embodiment the IL-1F5 polypeptide of the invention, comprises an amino acid sequence having a methionine at position ten of the amino acid sequence, position ten being relative to the N-terminal amino acid at position one of the amino acid sequence and an amino acid selected from the group consisting of valine and methionine at the N-terminal amino acid at position and a leucine at position two. In particular embodiments, the IL-1F5 polypeptide of the invention comprises at least 90%, at least 95%, at least 98% or at least 99% identity to SEQ ID NO 1 and a methionine at position ten of the amino acid sequence of the IL-1F5 polypeptide of the invention, position ten being relative to the N-terminal amino acid a position one. In some embodiments, the isolated IL-1F5 polypeptide of the invention antagonizes signal transduction/activation through IL-1Rrp2 more than the IL-1F5 polypeptide having the amino acid sequence of SEQ ID NO 1. In some embodiments, the isolated IL-1F5 polypeptide of the invention antagonizes signal transduction/activation through IL-1Rrp2 more than about 5 fold, 10 fold, 100 fold, 1,000 fold the level of antagonization of signal transduction/activation of the IL-1F5 polypeptide having the amino acid sequence of SEQ ID NO 1. The level of signal transduction/activation antagonization is measured according to the method described in Example 2A. In a particular embodiment, the isolated IL-1F5 polypeptide of the invention has a methionine at position ten of its amino acid sequence relative to the N-terminal amino acid at position one and comprises an amino acid sequence selected from the group consisting of:
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